1. Field of the Invention
This application relates generally to medical implant devices and methods of use, specifically relating to the preparation of an implantable device, the sterilization and storage of the device, and the use and delivery of the device. The material of the present invention may serve as an implantable material in order to aid tissue healing, serve as a void filler, prevent adhesions, and/or serve as a drug delivery vessel, among other beneficial uses.
2. Discussion of Related Art
Hydrogels may be formed from a variety of polymeric materials and are useful in a variety of biomedical applications, for example, wound management, soft contact lens construction, surgical applications, and drug delivery applications. To be suitable for implantation in a living being, the polymer material should be sterile to minimize opportunity for infection. An implantable polymer material may be manufactured through an aseptic manufacturing process, where care is taken to ensure sterility through the entirety of the manufacturing process, which is costly; or alternatively, sterilization may be accomplished by terminal sterilization, which is accompanied by the concomitant benefits of reduced cost and complexity. Terminal sterilization may be accomplished by methods known in the art (e.g., high energy radiation, heat, or chemical treatment).
It is commonly known that high energy sterilization (e.g., gamma irradiation, e beam radiation, etc.) results in changes to polymers (e.g., molecular weight loss, cross-linking, etc.) that may be undesirable in the final product. It is also known that these changes are more severe when the product is in a hydrated or solvated state. It is additionally known that forms of gas sterilization (e.g., plasma, ETO, etc.) usually result in few changes to the polymers, however gas sterilization techniques may only be applied to dry products. A need exists for an implantable dough, putty or gel capable of being terminally sterilized without deleterious effects.
In U.S. Pat. No. 5,409,703, McAnalley et al. describe a topical wound dressing made from a dried hydrogel of hydrophilic-hygroscopic polymer, which is capable of being sterilized. Upon topical application to the wound site, the dried hydrogel absorbs tissue fluids and changes from a solid state to a gel state wherein it adheres to the wound surface. McAnalley also describes that in applications where the traumatized area does not require exudate removal, the device may be applied as a hydrogel, by presoaking the dried gel in saline or other therapeutic liquid/suspension.
In U.S. patent application Ser. No. 10/616,055 Sawhney describes a polymer hydrogel to be introduced to a wound site as a relatively dry material in a substantially deswollen state; it may optionally contain therapeutic entities. Upon implantation and exposure to physiological fluids, the dried hydrogel absorbs fluids and undergoes a volumetric expansion, resulting in a sealing, plugging or augmentation of tissue.
In U.S. Pat. No. 5,645,583, Villain et al. disclose an injectable, non-resorbable permanent corneal implant of polyethylene oxide gel that has been crosslinked, wherein the implanted gel serves to replace or augment tissue. The crosslinked gel may be delivered through a syringe. The injectable gel material of Villain et al. serves to prevent the ingrowth or colonization of cells and vessels into the material in order to maintain optical clarity and allow removal of the implant. The Villain et al. disclosure describes the material as being subject to postoperative volume changes, depending on the electrolyte concentration of the original material, and the environment into which the implant is introduced. Villain et al. do not describe an implant that is a pre-operatively swollen rehydrated gel material, serving to encourage the ingrowth of tissue and cells into the resorbable structure.
Delmotte, in U.S. Pat. No. 6,599,515, describes the making of a fibrin sponge, created from a solution containing fibrin, wherein the fibrin undergoes partial clotting (modulated by the addition of thrombin to the solution) and is partially cross-linked, which is then dried by lyophilization. When rehydrated, the fibrin sponge material retains its structure, merely expanding in size as fluid is absorbed into the sponge. The fibrin sponge may be milled or ground into a small grain size particulate material, may be admixed with other solid particles, such as bone chips, and suspended in a viscous gel to form a glue or cement for filling a bone void. Preferably the mixture would be made as a paste or in a substantially liquid form, in order to ease application. Delmotte also describes the material of the invention being used as a bone substitute, wherein the fibrin sponge material of the invention is hydrated with a solution before use. The material described by Delmotte must be milled or ground into particles in order to allow the creation of a paste suitable for use in filling a bone void. Delmotte does not address the need for a material that does not require milling or grinding before the addition of a liquid or glue in creating a bone void filling material.
Bodmeir in US Application 2004/0010224 discloses the use of a porous lyophilized material, that when exposed to a solvent causes the dissolution of the material, and may form a viscous liquid that is able to be implanted into the body and serve as a drug depot. As the original solvent is removed from the material, the implanted viscous liquid will harden in the presence of aqueous fluids, such as a physiological environment. The implantable material described by Bodmeir undergoes a phase change, from liquid to solid once it is implanted. Bodmeir does not describe an implant that remains a putty or dough after implantation, until eventual resorption into the body.
Malson et al. in U.S. Pat. No. 4,772,419 describes a crosslinked hyaluronic acid (or salt thereof) gel material that may be formed into a shaped article by pressure-drying or freeze-drying. The crosslinked hyaluronic material may be stored dry, and implanted or placed upon a body in dry form, or alternatively after being rehydrated in a saline solution. The crosslinking present in the material causes the material to be rehydrated as a sponge, wherein the structure is maintained, rather than forming a flowable hydrogel or putty.
Kennedy et al. in U.S. Pat. No. 6,488,952 discloses a semisolid therapeutic delivery system for injection, deposition, or implantation within the body to deliver therapies to the body. The semisolid material is formed by application of heat to melt Glycerol Monooleate or other materials having similar physical/chemical properties with respect to viscosity/rigidity, then admixing a warm aqueous buffer solution to form a gel. To the gel is added the various therapies or particulate material for systemic or local delivery to the body once implanted. The viscosity may be varied by controlling water content. The gel of sufficient viscosity forms a malleable material that may be delivered and manipulated in an implant site. Kennedy et al. do not disclose a gel material that may be dried, and rehydrated for implantation without adding heat and/or heated solutions.
Hubbard in U.S. Pat. No. 6,432,437 discloses a biocompatible material for permanent soft tissue augmentation. The material is substantially non-resorbable, ceramic spheroidal particles that are implanted and serves as a scaffold to allow tissue ingrowth. The ceramic particles can be suspended for delivery in a lubricious polysaccharide gel carrier and lubricant. The composite material of ceramic particles and gel may be stored for an indefinite period without settling of the particles, provided that the ceramic particles are of a sufficiently small size, on the order of less than 125 microns. The gel material disclosed by Hubbard is sterilizable through autoclaving, although it suffers a reduction in viscosity. The gel material is unsuitable for gamma sterilization as the gel is destroyed. Hubbard does not disclose a gel material that may be readily gamma sterilized, stored dry, and then be rehydrated to form a viscous injectable putty or dough for implant.
Wolfinbarger in U.S. Pat. No. 5,531,791 describes an injectable/flowable viscous composite of demineralized bone material and a collagen carrier, for use in bone repair. The demineralized bone component may be stored separate from a dried or lyophilized collagen carrier matrix. The bone cement and the matrix may be rehydrated and mixed, immediately before implantation; alternatively, the composite materials may be stored as a wet mixture.
Wolfinbarger discloses a collagen matrix material that may be lyophilized for storage, and rehydrated by the sterile addition of saline solution and demineralized bone component to a final collagen concentration of one to two percent. The concentrations of collagen described by Wolfinbarger will solubilize simply by the addition of saline, without requiring additional techniques to achieve solubilization.
Damien et al. in WO9835653 disclose a dry osteoinductive composition made by the process of admixing collagen, acid, osteoinductive material, and water to form a gel, which is lyophilized. The resulting dried gel is described as being able to withstand dry sterilization, such as gamma radiation sterilization or chemical treatment, and avoids chemical reactions that would otherwise occur when sterilizing wet material through similar techniques. The lyophilized material described by Damien et al. may be rehydrated simply by adding water to form a gel. WO9835653 discloses a collagen gel made by solubilizing 100 mg of collagen in 7.4 mL aqueous acid solution (1.35% collagen w/v), which is then lyophilized. A 15 mg sample of the dried collagen material is then rehydrated to a similar concentration as the original gel, as 1.14 mL of water is simply added to 15 mg of dried collagen material (1.31% collagen w/v), forming the rehydrated gel.
A need exists for an implantable material that is suitable for dry sterilization techniques, eliminating the need to be aseptically processed, thereby reducing costs. Further, a need exists for a dried, sterilized material suitable for extended storage, without settling or stratification of the material or fear of degradation, unlike a wet material. The material, to be most beneficial, should be deliverable into the body as an injectable viscous putty or dough.
Chu in U.S. Pat. No. 4,743,229 discloses a syringe system for preparing inductive and conductive bone repair compositions. The device described by Chu allows the mixing of a substantially uniform collagen/mineral bone implant preparation, incorporating a pair of syringes facing each other, with a connective adapter arranged between the delivery ends. By application of force on the barrel containing the collagen solution, the fluid is forced into the barrel of the other syringe containing the particulate material. Air within the mineral particulate is displaced by the inflow of fluid, and escapes through a porous barrier at the opposite end of the particulate material syringe. Chu does not disclose or contemplate a phase transition during mixing as the collagen solution is directed into the particulate material.
A need exists for a high viscosity material suitable for injection or in-situ molding supplied in dry form, which is readily and quickly rehydratable or resolvable upon addition of fluid (e.g., blood, saline, water, acetone, etc.), which facilitates cellular ingrowth. It is the intent of this invention to overcome these and other shortcomings of the prior art.